期刊
BIOINFORMATICS
卷 32, 期 4, 页码 549-556出版社
OXFORD UNIV PRESS
DOI: 10.1093/bioinformatics/btv619
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资金
- National Institutes of Health Common Fund [U41HG006941]
- Government of Canada via the International Development Research Centre (IDRC) through the African Institute for Mathematical Sciences - Next Einstein Initiative (AIMS-NEI)
Motivation: Despite numerous successful Genome-wide Association Studies (GWAS), detecting variants that have low disease risk still poses a challenge. GWAS may miss disease genes with weak genetic effects or strong epistatic effects due to the single-marker testing approach commonly used. GWAS may thus generate false negative or inconclusive results, suggesting the need for novel methods to combine effects of single nucleotide polymorphisms within a gene to increase the likelihood of fully characterizing the susceptibility gene. Results: We developed ancGWAS, an algebraic graph-based centrality measure that accounts for linkage disequilibrium in identifying significant disease sub-networks by integrating the association signal from GWAS data sets into the human protein-protein interaction (PPI) network. We validated ancGWAS using an association study result from a breast cancer data set and the simulation of interactive disease loci in the simulation of a complex admixed population, as well as pathway-based GWAS simulation. This new approach holds promise for deconvoluting the interactions between genes underlying the pathogenesis of complex diseases. Results obtained yield a novel central breast cancer sub-network of the human interactome implicated in the proteoglycan syndecan-mediated signaling events pathway which is known to play a major role in mesenchymal tumor cell proliferation, thus providing further insights into breast cancer pathogenesis.
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